Loss of Rb overrides the requirement for ERK activity for cell proliferation.
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The Ras GTPase is a critical transducer of mitogenic signals ultimately leading to inactivation of the retinoblastoma (Rb) protein, but the molecular basis underlying Ras-dependent control of cell cycle kinetics remains to a great extent unknown. In an effort to further elucidate the role of Ras activation in cell cycle control, we have studied the role of the downstream Mek-ERK pathway in facilitating exit from the quiescent G0 state and passage through the G1/S transition. We have adopted a genetic approach in combination with U0126, an inhibitor of Mek activation to study the role of Mek in cell cycle progression. Here we report that whereas wild-type (Wt) mouse embryo fibroblasts (MEFs) depend on ERK activation to enter the cell cycle, Rb-deficient (Rb(-/-)) MEFs have a reduced requirement for ERK signalling. Indeed in the presence of U0126 we found that Rb-null MEFs can exit G0, make the G1/S transition and proliferate. Analysis of Rb-deficient tumour cell lines also revealed a reduced requirement for ERK signalling in asynchronous growth. We discuss the molecular mechanism that may underlie this escape from MAP kinase signalling.
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Tumor Cells, Cultured
Mitogen-Activated Protein Kinase Kinases
Mitogen-Activated Protein Kinases
MAP Kinase Signaling System
Gene Expression Regulation
Cyclin-Dependent Kinase 4
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Journal of cell science, 2002, 115 (Pt 23), pp. 4607 - 4616
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